Novel oxindole compounds inhibit the aggregation of amyloidogenic proteins associated with neurodegenerative diseases

• Published in: Biochimica et biophysica acta. General subjects Vol. 1866; no. 5; p. 130114
• Main Authors: Kimura, Shintaro, Kamishina, Hiroaki, Hirata, Yoko, Furuta, Kyoji, Furukawa, Yoshiaki, Yamato, Osamu, Maeda, Sadatoshi, Kamatari, Yuji O.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2022
• Subjects: Alzheimer disease; Amyloidogenic Proteins; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Animals; cognitive disorders; Dogs; drugs; fluorescence; Humans; mutants; mutation; Neurodegenerative Diseases - genetics; Oxindole compounds; Oxindoles - pharmacology; Prion protein; prions; Protein aggregation; superoxide dismutase; Superoxide dismutase 1; Superoxide Dismutase-1 - genetics; therapeutics; Amyloidogenic proteins; ThT; Protein aggregation; Oxindole compounds; ALS; DM; DAPI; ER; SOD1; PrP; hSOD1; Aβ; LDH; Superoxide dismutase 1; cSOD1; hPrP; FBS; IC50; Prion protein; GdnHCl; TEM
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2022.130114

Amyloidogenic proteins form aggregates in cells, thereby leading to neurodegenerative disorders, including Alzheimer's and prion's disease, amyotrophic lateral sclerosis (ALS) in humans, and degenerative myelopathy (DM) and cognitive dysfunction in dogs. Hence, many small-molecule compounds have been screened to examine their inhibitory effects on amyloidogenic protein aggregation. However, no effective drug suitable for transition to clinical use has been found. Here we examined several novel oxindole compounds (GIF compounds) for their inhibitory effects on aggregate formation of the canine mutant superoxide dismutase 1 (cSOD1 E40K), a causative mutation resulting in DM, using Thioflavin-T fluorescence. Most GIF compounds inhibited the aggregation of cSOD1 E40K. Among the compounds, GIF-0854-r and GIF-0890-r were most effective. Their inhibitory effects were also observed in cSOD1 E40K-transfected cells. Additionally, GIF-0890-r effectively inhibited the aggregate formation of human SOD1 G93A, a causative mutation of ALS. GIF-0827-r and GIF-0856-r also effectively inhibited aggregate formation of human prion protein (hPrP). Subsequently, the correlation between their inhibitory effects on cSOD1 and hPrP aggregation was shown, indicating GIF compounds inhibited the aggregate formation of multiple amyloidogenic proteins. Conclusively, the novel oxindole compounds (GIF-0827-r, GIF-0854-r, GIF-0856-r, and GIF-0890-r) are proposed as useful therapeutic candidates for amyloidogenic neurodegenerative disorders. •The novel oxindole compounds, GIF compounds, inhibited aggregation of the canine superoxide dismutase1 protein associated with canine degenerative myelopathy.•The inhibitory effects were also observed in multiple amyloidogenic proteins including the human superoxide dismutase 1 protein and the prion protein.•GIF compounds inhibited aggregation of multiple amyloidogenic proteins. Those might be candidates for multiple neurodegenerative disorders.